bims-mecosi Biomed News
on Membrane contact sites
Issue of 2025–09–07
seventeen papers selected by
Verena Kohler, Umeå University
  1. Mitochondria-ER contact site components regulate the formation and localization of specialized high-capacity mitochondria in the C. elegans anchor cell.
  2. Via Proteins and Lipids - Versatility of VAPs at Dynamic Membrane Contact Sites.
  3. MCS Ultrastructural Analyses Using Electron Microscopy.
  4. Acyl-coA binding protein AcbdA regulates peroxisome hitchhiking on early endosomes.
  5. Acyl-coA binding protein AcbdA is required for peroxisome hitchhiking on early endosomes in Aspergillus nidulans.
  6. Bipartite Genetically Encoded Biosensors to Sense Calcium Ion Dynamics at Membrane-Membrane Contact Sites.
  7. Membrane contact sites between chloroplasts and the pathogen interface underpin plant focal immune responses.
  8. Organelle bridges and nanodomain partitioning govern targeting of membrane-embedded proteins to lipid droplets.
  9. A Yeast-Based In Vivo Assay Complements In Vitro and In Silico Approaches to Characterize Sterol-Binding by Saccharomyces cerevisiae Lam/Ltc Proteins.
  10. Editorial: Calcium homeostasis and cardiovascular health: mechanisms and therapeutic insights.
  11. Tetramethylpyrazine improves the structure and function of mitochondrial-associated endoplasmic reticulum membrane and liver fibrosis.
  12. Melatonin regulates accumulation of lipids in the liver via the IP3R on the mitochondria-associated membranes (MAMs).
  13. Multiple interactions recruit BLTP2 to ER-PM contacts to control plasma membrane dynamics.
  14. ER stress disrupts MFN2-related mitophagy via HRD1-PINK1/ parkin axis in bovine embryos.
  15. Mitophagy Activation by N-Acetylcysteine Protects against Mic60 Deficiency-Induced Auditory Neuropathy.
  16. The organelle tethering protein PDZD8 regulates endolysosomal maturation and TLR9-NF-κB signaling in cisplatin-induced acute kidney injury.
  17. Integrated control of cancer stemness by σ1 receptor in advanced prostate cancer.
  1. MicroPubl Biol. 2025 ;2025
    Mitochondria-ER contact site components regulate the formation and localization of specialized high-capacity mitochondria in the C. elegans anchor cell.
    Isabel W Kenny-Ganzert, David R Sherwood.
      Mitochondria-endoplasmic reticulum contact sites (MERCS) play crucial roles in mediating calcium signaling and lipid metabolism, and regulate mitochondrial morphology, function, and quality control. Recent studies have found that the C. elegans anchor cell (AC) harbors a specialized pool of high-capacity mitochondria that localize to the invasive front and are enriched with electron transport chain proteins to generate high ATP levels to fuel invasion. We conducted an RNAi screen of 59 MERCS-encoding components and identified over 30 required for high-capacity mitochondria formation. Our results suggest that MERCS may play a key role in the formation of specialized high-capacity mitochondria.
    DOI:  https://doi.org/10.17912/micropub.biology.001679
  2. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251372673
    Via Proteins and Lipids - Versatility of VAPs at Dynamic Membrane Contact Sites.
    Dan Zhang.
      VAMP-associated proteins (VAPs) are highly conserved, endoplasmic reticulum (ER)-resident receptors that tether the ER to various membrane compartments in eukaryotic cells. Each VAP contains a transmembrane helix at its extreme C-terminus and a conserved N-terminal major sperm protein (MSP) domain that mediates various cytosolic interactions via both protein and lipid binding. Here, I question the fundamental difference between protein- and lipid-based associations in VAP-driven membrane contact site (MCS) formation and function - could the lipid affinity of VAPs be an overlooked factor in MCS dynamic regulation?
    Keywords:  FFAT-related motif; MSP domain; VAP; anionic phospholipid; membrane contact plasticity; membrane contact site
    DOI:  https://doi.org/10.1177/25152564251372673
  3. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251372668
    MCS Ultrastructural Analyses Using Electron Microscopy.
    Atsuki Nara.
      Membrane contact sites (MCSs) are microdomains that exchange ions and lipids between the membranes of two organelles. They facilitate the exchange of metabolites and act as a site for intracellular communication through material transport. Because of the important physiological significance of MCSs in localizing the exchange of substances and metabolic regulation, they are considered to play an important role in cell biology. Understanding MCS structure is essential for analyzing how substances move to and from each organelle. Several methods have been developed to analyze MCS function, with electron microscopy (EM) being the predominant technique when structural detail is needed. In this review, we summarize the ultrastructure of MCSs and how EM can be used to determine their role in cell biology.
    Keywords:  ER; autophagosome; contact; electron microscopy; endosome; membrane contact sites; mitochondria; nucleus; plasma membrane; tether
    DOI:  https://doi.org/10.1177/25152564251372668
  4. bioRxiv. 2025 Apr 23. pii: 2025.04.17.649231. [Epub ahead of print]
    Acyl-coA binding protein AcbdA regulates peroxisome hitchhiking on early endosomes.
    Bellana Driscoll, Madison B Fountain, Isabella N Gates, Reihane Abdollahi, Allison M Langley, Matthew B Owens, Jenna R Christensen, John Salogiannis.
      Motor-driven transport on microtubules is critical for distributing organelles throughout the cell. Most commonly, organelle movement is mediated by cargo adaptors, proteins on the surface of an organelle that directly recruit microtubule-based motors. An alternative mechanism called hitchhiking was recently discovered: some organelles move, not by recruiting the motors directly, but instead by using membrane contact sites to attach to motor-driven vesicles and hitchhike along microtubules. Organelle hitchhiking is observed across fungi and animals. In filamentous fungi, nearly all peroxisomes move by hitchhiking on early endosomes (EEs). In the fungus Aspergillus nidulans, EE-associated linker proteins PxdA and DipA are critical for establishing EE-peroxisome membrane contact sites required for peroxisome movement. How peroxisomes recognize this subset of EEs and what peroxisome-membrane proteins exist that can interact with EEs is not known. Here, we undertook a forward mutagenesis screen to identify such proteins. We discovered an acyl-coA binding (ACB) domain-containing protein AcbdA/AN1062 that localizes to peroxisomes via its tail-anchored transmembrane domain (TMD). Deleting the AcbdA gene or only its N-terminal ACB domain perturbs the movement and distribution of peroxisomes. Importantly, AcbdA is not required for the movement of EEs or for the recruitment of PxdA and DipA on EEs. Fatty acid (FA)-induced increases in peroxisome movement require AcbdA, suggesting that peroxisome hitchhiking on EEs is coupled to FA metabolism. Mutating a conserved FFAT motif, predicted to interact with the endoplasmic reticulum (ER), has no effect on peroxisome movement. Taken together, our data indicate that AcbdA is a peroxisome-membrane protein required to tether peroxisomes to EEs during hitchhiking. AcbdA's involvement in peroxisome-EE contact site formation represents a divergence from known functions of Acbd4/5 proteins and adds layers to our understanding of the functionality of the Acbd4/5 family of proteins.
    DOI:  https://doi.org/10.1101/2025.04.17.649231
  5. Mol Biol Cell. 2025 Sep 03. mbcE25040186
    Acyl-coA binding protein AcbdA is required for peroxisome hitchhiking on early endosomes in Aspergillus nidulans.
    Bellana Driscoll, Madison B Fountain, Isabella N Gates, Reihane Abdollahi, Allison M Langley, Matthew B Owens, Jenna R Christensen, John Salogiannis.
      Motor-driven transport on microtubules is critical for distributing organelles throughout the cell. Most commonly, organelle movement is mediated by cargo adaptors, proteins on the surface of an organelle that directly recruit microtubule-based motors. An alternative mechanism called hitchhiking was recently discovered: some organelles move, not by recruiting the motors directly, but instead by using membrane contact sites to attach to motor-driven vesicles and hitchhike along microtubules. Organelle hitchhiking is observed across fungi and animals. In filamentous fungi, nearly all peroxisomes move by hitchhiking on early endosomes (EEs). In the fungus Aspergillus nidulans, EE-associated linker proteins PxdA and DipA are critical for establishing EE-peroxisome membrane contact sites required for peroxisome movement. Whether peroxisome-membrane proteins exist that regulate peroxisome hitchhiking on EEs is not known. Through a forward mutagenesis screen, we discovered an acyl-coA binding (ACB) domain-containing protein AcbdA/AN1062 that localizes to peroxisomes via its tail-anchored transmembrane domain (TMD). Deleting the AcbdA gene or only its N-terminal ACB domain perturbs the movement and distribution of peroxisomes. Importantly, AcbdA is not required for the movement of EEs or for the recruitment of PxdA and DipA on EEs. Fatty acid (FA)-induced increases in peroxisome movement require AcbdA, suggesting that peroxisome hitchhiking on EEs is coupled to FA metabolism. Mutating a conserved FFAT motif, predicted to interact with the endoplasmic reticulum (ER), has no effect on peroxisome movement. Taken together, our data indicate that AcbdA is a peroxisome-membrane protein required for peroxisome hitchhiking on EEs. AcbdA's involvement in peroxisome hitchhiking represents a divergence from known functions of Acbd4/5 proteins and adds layers to our understanding of the functionality of the Acbd4/5 family of proteins. [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E25-04-0186
  6. Anal Chem. 2025 Sep 01.
    Bipartite Genetically Encoded Biosensors to Sense Calcium Ion Dynamics at Membrane-Membrane Contact Sites.
    Issei Yamaguchi, Lucia Barazzuol, Giulia Dematteis, Wenchao Zhu, Yurong Wen, Mikhail Drobizhev, Dmitry Lim, Robert E Campbell, Tito Calì, Yusuke Nasu.
      Self-complementing bipartite fluorescent proteins (FPs) are useful tools for the detection of protein-protein proximity and for localizing fluorophores to membrane-membrane contact sites. Here, we report versions of circularly permuted green FP (GFP), red FP (RFP), and mNeonGreen (NG), which are split into a large fragment composed of nine β-strands and a small fragment composed of two β-strands. In each case, the large and small fragments can associate in live cells to form the complete 11-stranded FP β-barrel. We further converted each of these three self-complementing FPs into bipartite calcium ion (Ca2+) biosensors. We demonstrate that appropriately targeted versions of these split FPs, and split FP-based biosensors, can be functionally assembled at membrane-membrane contact sites. We employ the bipartite NG-based Ca2+ biosensor for visualization of pharmacologically induced Ca2+ release at mitochondria-endoplasmic reticulum contact sites (MERCs).
    DOI:  https://doi.org/10.1021/acs.analchem.5c03831
  7. Plant Cell. 2025 Sep 05. pii: koaf214. [Epub ahead of print]
    Membrane contact sites between chloroplasts and the pathogen interface underpin plant focal immune responses.
    Enoch Lok Him Yuen, Zachary Savage, Vojtěch Pražák, Zhongyuan Liu, Vanda Adamkova, Freddie King, Cristina Vuolo, Tarhan Ibrahim, Yijun Wang, Saskia Jenkins, Yuanyang Zhou, Yasin Tumtas, Jessica Lee Erickson, Jennifer Prautsch, Andrada I Balmez, Johannes Stuttmann, Cian Duggan, Francesco Rivetti, Camilla Molinari, David C A Gaboriau, Philip Carella, Xiaohong Zhuang, Martin Schattat, Tolga O Bozkurt.
      Communication between cellular organelles is essential for mounting effective innate immune responses. The transport of organelles to pathogen penetration sites and their assembly around the host membrane, which delineates the plant-pathogen interface, are well-documented. However, whether organelles associate with these specialized interfaces, and the extent to which this process contributes to immunity, remain unknown. Here, we discovered defense-related membrane contact sites (MCS) comprising a membrane tethering complex between chloroplasts and the extrahaustorial membrane (EHM) surrounding the haustorium of the pathogen Phytophthora infestans in Nicotiana benthamiana. The assembly of this complex involves association between the chloroplast outer envelope protein CHLOROPLAST UNUSUAL POSITIONING 1 (CHUP1) and its plasma membrane-associated partner KINESIN-LIKE PROTEIN FOR ACTIN-BASED CHLOROPLAST MOVEMENT 1 (KAC1). Our biochemical assays revealed that CHUP1 and KAC1 interact, and infection cell biology assays demonstrated their co-accumulation in foci where chloroplasts contact the EHM. Genetic depletion of CHUP1 or KAC1 reduces the focal deposition of callose around the haustorium without affecting other core immune processes. Our findings suggest that the chloroplast-EHM attachment complex promotes plant focal immunity, revealing key components and their potential roles in the deposition of defense materials at the pathogen interface. These results advance our understanding of organelle-mediated immunity and highlight the significance of MCS in plant-pathogen interactions.
    DOI:  https://doi.org/10.1093/plcell/koaf214
  8. bioRxiv. 2025 Aug 20. pii: 2024.08.27.610018. [Epub ahead of print]
    Organelle bridges and nanodomain partitioning govern targeting of membrane-embedded proteins to lipid droplets.
    Arda Mizrak, Jacob Kæstel-Hansen, Jessica Matthias, J Wade Harper, Nikos S Hatzakis, Robert V Farese, Tobias C Walther.
      Numerous metabolic enzymes translocate from the ER membrane bilayer to the lipid droplet (LD) monolayer, where they perform essential functions. Mislocalization of certain LD-targeted membrane proteins, including HSD17B13 and PNPLA3, is implicated in metabolic dysfunction-associated steatotic liver disease (MASLD). However, the mechanisms governing the trafficking and accumulation of ER proteins on LDs remain poorly understood. Here, using MINFLUX and HILO single-molecule tracking combined with machine learning, we show that HSD17B13, GPAT4, and the model cargo LiveDrop diffuse at comparable speeds in the ER and on LDs, but become nano-confined upon reaching the LD surface. Mechanistic dissection of LiveDrop targeting revealed that this confinement, along with protein accumulation on LDs, depends on specific residues within its targeting motif. These residues mediate preferential and repeated interactions with nanoscale membrane domains, suggesting that LD-targeted proteins selectively partition into distinct lipid-protein environments that transiently retain and concentrate them at the LD surface. Single-molecule trajectories further revealed bidirectional trafficking of LiveDrop across seipin-containing ER-LD bridges, providing direct evidence for lateral protein transfer across membrane contact sites. These findings establish nanodomain-based confinement as a key mechanism driving selective protein accumulation on LDs and reveal how membrane bridges between organelles facilitate protein sorting.
    DOI:  https://doi.org/10.1101/2024.08.27.610018
  9. J Biol Chem. 2025 Sep 01. pii: S0021-9258(25)02515-3. [Epub ahead of print] 110663
    A Yeast-Based In Vivo Assay Complements In Vitro and In Silico Approaches to Characterize Sterol-Binding by Saccharomyces cerevisiae Lam/Ltc Proteins.
    Ola El Atab, Barkha Gupta, Zhu Han, Rabih Darwiche, Stéphanie Cottier, Jiri Stribny, Roger Schneiter.
      Cellular membranes maintain distinct lipid compositions, with sterols enriched in the plasma membrane despite their synthesis in the endoplasmic reticulum (ER). This distribution relies on vesicular and non-vesicular transport, the latter facilitated by lipid transfer proteins (LTPs) at membrane contact sites. In yeast, the Lam/Ltc family of LTPs is critical for sterol transport. To characterize their sterol-binding properties in a cellular context, we developed a yeast-based in vivo assay using Saccharomyces cerevisiae. Here, sterol-binding proteins, fused to signal sequences, extract and export radiolabeled cholesterol from the luminal compartment of the secretory pathway to the culture medium, offering a qualitative measure of binding capacity. We demonstrate that yeast Lam/Ltc proteins (Ysp1, Ysp2, Lam4, Lam5, Lam6) and their StARkin domains efficiently extract sterols, complementing the activity of known LTPs (Pry1, NPC2, Osh4, STARD1). In vitro microscale thermophoresis (MST) and in silico docking confirmed low micromolar to nanomolar sterol affinities. Notably, Lam6 binds phosphatidylserine through its GRAM domain, with synergistic binding to membranes containing both phosphatidylserine and ergosterol. While limited by its qualitative nature and luminal specificity, the in vivo sterol binding assay complements in vitro methods, providing a robust tool to study LTPs in a cellular environment. These findings enhance our understanding of Lam/Ltc protein function and highlight the assay's potential for characterizing known and orphan LTPs.
    Keywords:  Lam/Ltc proteins; Lipid transfer proteins; Saccharomyces cerevisiae; StARkin domain; in vivo assay; membrane contact sites; microscale thermophoresis; phosphatidylserine; sterol binding
    DOI:  https://doi.org/10.1016/j.jbc.2025.110663
  10. Front Endocrinol (Lausanne). 2025 ;16 1679610
    Editorial: Calcium homeostasis and cardiovascular health: mechanisms and therapeutic insights.
    Ki Ho Park, Bowen Wang.
      
    Keywords:  atherosclerosis; calcium homeostasis; cardiovascular disease; cellular senescence; irisin; mitochondria-associated membranes (MAMs); non-alcoholic fatty liver disease (NAFLD); vascular calcification
    DOI:  https://doi.org/10.3389/fendo.2025.1679610
  11. J Adv Res. 2025 Sep 03. pii: S2090-1232(25)00686-1. [Epub ahead of print]
    Tetramethylpyrazine improves the structure and function of mitochondrial-associated endoplasmic reticulum membrane and liver fibrosis.
    Kaihong Xie, Jianzhi Wu, Liping Gong, Wenqing Qin, Zixuan Huo, Yinhao Zhang, Jiaorong Qu, Runping Liu, Jianan Li, Jianhang Lan, Yufei Li, Ranyi Luo, Xiaojiaoyang Li.
       INTRODUCTION: Morphological and functional abnormalities of mitochondrial-associated endoplasmic reticulum (ER) membrane (MAM) have emerged as a key mediator of organelle dysfunction during liver fibrosis. Tetramethylpyrazine (TMP) was investigated as a potential therapy for liver fibrosis with an unclear mechanism.
    OBJECTIVES: Considering the changes of MAM quantity and gap distance during liver fibrosis, we aimed to investigate the underlying mechanisms and their potential as therapeutic targets for TMP in inhibiting liver fibrosis.
    METHODS: Through different sequencing techniques and a series of molecular biology experiments, we explored the effects and mechanisms of TMP in CCl4-induced fibrosis models both in vivo and in vitro and examined key signaling in patients with fibrosis.
    RESULTS: An aberrant increase in the numbers of MAM and drastic alterations in the morphology of ER and mitochondria were accompanied by a substantial influx of Ca2+ from the ER into mitochondria under fibrotic conditions. These changes were largely restored by TMP. Further isolation of distinct cellular fractions revealed that CCl4 caused mis-localization and local concentration of MAM proteins, primarily by suppressing mitofusin 2 (MFN2). TMP directly bound to and stimulated MFN2 expression by activating transcription and inhibiting K79 ubiquitination-mediated degradation, which promoted the interaction and function of MFN2-sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2) complex for reversing Ca2+ overload in mitochondria. Notably, findings in fibrosis patients and hepatic MFN2 knockdown mice further underscored the crucial role of MFN2-mediated normalization of MAM in improving liver fibrosis and the therapeutic effects of TMP.
    CONCLUSION: Here, we highlight the therapeutic potential of TMP in liver fibrosis by elucidating its role in repairing hepatic MAM.
    Keywords:  Liver fibrosis; MAM; MFN2; SERCA2
    DOI:  https://doi.org/10.1016/j.jare.2025.09.003
  12. Cell Signal. 2025 Sep 01. pii: S0898-6568(25)00524-8. [Epub ahead of print]136 112109
    Melatonin regulates accumulation of lipids in the liver via the IP3R on the mitochondria-associated membranes (MAMs).
    Mei-Yu Jin, Hao Yu, Yun-Fei Wei, Xin Ma, Xu-Ming Deng, Jian-Feng Wang, Hai-Hua Feng.
      Nonalcoholic fatty liver disease (NAFLD) is a common metabolic disease of the liver that can progress to hepatitis, cirrhosis, and even cancer in extreme cases. In this study, we investigated the effect of Melatonin (Mel) on lipid accumulation and explored the molecular mechanism behind it. Mel treatment reduced lipid accumulation and enhanced autophagy in oleic acid (OA) + palmitic acid (PA)-induced cells. Notably, Mel could regulate the inositol 1,4,5-triphosphate receptor (IP3R) pathway in OA + PA-induced cells and form hydrogen bonds with the IP3R protein. Interestingly, when cells were transfected with siRNA-IP3R, the regulatory effects of Mel on lipid accumulation and autophagy were lost in OA + PA-induced cells. We found that this might be due to Mel-regulated IP3R acting on the AMPK/mTOR pathway rather than on Bcl-2 and Beclin1. More importantly, we found that Mel could reduce the increase in MAMs caused by OA + PA-induced cells. And the integrity of MAMs could influence the role of Mel in regulating IP3R, as well as the regulation of lipid accumulation and autophagy by Mel. In summary, this study revealed that Mel has the function of ameliorating lipid accumulation by regulating the expression of IP3R on MAMs. This is because Mel-regulated IP3R can induce autophagy and alleviate lipid accumulation. This provides a new theoretical basis for Mel to regulate lipid accumulation.
    Keywords:  AMPK/mTOR; IP3R; Lipid accumulation; MAMs; Melatonin
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112109
  13. J Cell Biol. 2025 Sep 03. pii: e202504027. [Epub ahead of print]224(11):
    Multiple interactions recruit BLTP2 to ER-PM contacts to control plasma membrane dynamics.
    Anbang Dai, Peng Xu, Chase Amos, Kenshiro Fujise, Yumei Wu, Han Yang, Julia N Eisen, Andrés Guillén-Samander, Pietro De Camilli.
      BLTP2/KIAA0100, a bridge-like lipid transfer protein, was reported to localize at contacts of the ER with either the plasma membrane (PM) or recycling tubular endosomes depending on the cell type. Our findings suggest that mediating bulk lipid transport between the ER and the PM is a key function of this protein, as BLTP2 tethers the ER to tubular endosomes only after they become continuous with the PM and that it also tethers the ER to macropinosomes in the process of fusing with the PM. We further identify interactions underlying binding of BLTP2 to the PM, including phosphoinositides, the adaptor proteins FAM102A/FAM102B, and N-BAR domain proteins at membrane-connected tubules. The absence of BLTP2 results in the accumulation of intracellular vacuoles, many of which are connected to the PM, pointing to a role of the lipid transport function of BLTP2 in the control of PM dynamics.
    DOI:  https://doi.org/10.1083/jcb.202504027
  14. Theriogenology. 2025 Aug 28. pii: S0093-691X(25)00385-1. [Epub ahead of print]249 117659
    ER stress disrupts MFN2-related mitophagy via HRD1-PINK1/ parkin axis in bovine embryos.
    Shu-Ming Shi, Li-Ying Liu, Zhi-Chao Chi, Lin-Yi Qu, Jing-Hang Li, Guan-Lin Jia, Yu-Yan He, Yong-Xun Jin, Ming-Jun Zhang, Xian-Feng Yu.
      The endoplasmic reticulum and mitochondria are interconnected through the MAM structure, and mitochondrial fusion protein 2 (MFN2) is a key regulatory factor. In this study, tunicamycin (TM) was used to induce endoplasmic reticulum stress in bovine embryos to explore its effects on MFN2 expression, mitochondrial function and mitochondrial autophagy. The results showed that TM treatment significantly reduced the blastocyst rate and proliferation capacity of embryos, inhibited the expression of pluripotency genes (SOX2, CDX2, OCT4), and upregulated key proteins of the UPR pathway. The expression of MFN2 and MAM region E3 ubiquitin ligase (HRD1) was significantly increased, PINK1 expression was downregulated, and Parkin localization on the mitochondrial membrane was reduced. Colocalization analysis and the reduction of LC3-II ratio indicated that mitochondrial autophagy was blocked. At the same time, mitochondrial membrane potential, ATP content and functional genes (PGC-1, TFAM) expression were downregulated, OXPHOS key enzymes were inhibited, and glycolysis was compensated. The mitochondrial apoptosis marker cytochrome C was released, Caspase3 was upregulated, and the PI positive rate increased. In summary, ER stress inhibits mitophagy through HRD1 -mediated PINK1 degradation, leading to the accumulation of mitochondrial damage, aggravating energy metabolism disorders and apoptosis, and ultimately inhibiting the in vitro development of bovine embryos.
    Keywords:  Bovine embryo; Endoplasmic reticulum stress; MFN2; Mitochondrial dysfunction; Mitophagy
    DOI:  https://doi.org/10.1016/j.theriogenology.2025.117659
  15. Neurosci Bull. 2025 Aug 30.
    Mitophagy Activation by N-Acetylcysteine Protects against Mic60 Deficiency-Induced Auditory Neuropathy.
    Yilin Sun, Chunying Liu, Yakun Liang, An Lv, Wang Nie, Shuyue Bao, Xiaoyi Li, Jing Zhou, Weimin Tong, Yong Tao, Xueling Wang, Tingting Dong.
      Auditory neuropathy (AN) is a sensorineural hearing loss that impairs speech perception, but its mechanisms and treatments remain limited. Mic60, essential for the mitochondrial contact site and cristae organizing system, is linked to neurological disorders, yet its role in the auditory system remains unclear. We demonstrate that Mic60+/- mice develop progressive hearing loss from 6 months of age, with reduced auditory brainstem response amplitudes despite preserved outer hair cell function, consistent with AN. Mitochondrial abnormalities in spiral ganglion neurons (SGNs) emerge by 3 months, followed by mitochondrial loss and SGN degeneration, indicating progressive auditory neuron dysfunction. In vitro, Mic60 deficiency disrupts mitochondrial respiration, reversible by N-acetylcysteine (NAC). NAC treatment preserves mitochondrial integrity and rescues hearing by enhancing mitophagy. Our findings establish Mic60+/- mice as an AN animal model, highlight the role of Mic60 in the mitochondria of primary auditory neurons, and identify NAC as a potential AN treatment.
    Keywords:  Antioxidant; Auditory neuropathy; Mic60; Mitochondria; Mitophagy; N-acetylcysteine
    DOI:  https://doi.org/10.1007/s12264-025-01485-2
  16. Am J Physiol Renal Physiol. 2025 Sep 02.
    The organelle tethering protein PDZD8 regulates endolysosomal maturation and TLR9-NF-κB signaling in cisplatin-induced acute kidney injury.
    Yuto Takenaka, Hiroshi Maekawa, Yu Ah Hong, Midori Sakashita, Qi Li, Chigusa Kitayama, Koki Nakamura, Madina Saipidin, Jin Shang, Yusuke Hirabayashi, Masaomi Nangaku, Reiko Inagi.
      Acute kidney injury (AKI) is a life-threatening condition with high morbidity and mortality, characterized by inflammation linked to organelle stress. Despite its clinical significance, effective therapies remain limited. While organelle dysfunction is recognized as a driver of inflammation in AKI, the role of inter-organelle communication in this process remains poorly understood. PDZD8, a tethering protein on the endoplasmic reticulum (ER), facilitates ER-endolysosome contact that is essential for endolysosomal maturation. The mature endolysosome is a prerequisite for activating the DNA-sensing innate immune receptor, Toll-like receptor 9 (TLR9). Here, we investigated the role of PDZD8 in the TLR9-NF-κB pathway during AKI using Pdzd8 knockout (KO) mice and in vitro knockdown in human proximal tubular cells (PTCs). Pdzd8 KO mice showed reduced severity of cisplatin-induced AKI and reduced activation of the NF-κB pathway. Mechanistically, PDZD8 knockdown in PTCs impaired endolysosomal maturation and acidification. This functional disruption impeded the proper translocation of TLR9 to endolysosomes, thereby inhibiting the signaling cascade leading to NF-κB activation. Notably, PDZD8 knockdown did not alter mitochondrial morphology or the cytosolic leakage of mitochondrial DNA, an endogenous ligand for TLR9. These findings indicate that PDZD8 is crucial for maintaining endolysosomal homeostasis and regulating the TLR9-NF-κB pathway in cisplatin-induced tubular injury.
    Keywords:  PDZD8; acute kidney injury; cisplatin; endolysosome; organelle contact sites
    DOI:  https://doi.org/10.1152/ajprenal.00020.2025
  17. Oncogene. 2025 Sep 02.
    Integrated control of cancer stemness by σ1 receptor in advanced prostate cancer.
    Gianluca Civenni, Giada Sandrini, Jessica Merulla, Carola Musumeci, Elisa Federici, Arianna Vallegra, Aleksandra Kokanovic, Simone Mosole, Dheeraj Shinde, Elisa Sorrenti, Alyssa J J Paganoni, Martina Marchetti, Riccardo Valzelli, Domenico Albino, Matteo Pecoraro, Andrea Rinaldi, Marco Bolis, Roger Geiger, Tobias Winge, Catharina Holtschulte, Erik Laurini, Sabrina Pricl, Giuseppina M Carbone, Bernhard Wünsch, Carlo V Catapano.
      Cancer stem cells (CSCs) are pervasively present in human cancers and have a fundamental role in treatment failure and disease recurrence. Identifying critical elements that sustain the CSC phenotype may lead to novel strategies for cancer treatment. Here, we provide evidence of an essential link between the σ1 receptor (σ1R), a ligand-regulated chaperone protein residing preferentially at the endoplasmic reticulum-mitochondria contact sites, and CSCs in castration-resistant prostate cancers (CRPCs). Integrating functional assays in multiple preclinical models with transcriptomic and proteomic data, we found that σ1R controls CSC self-renewal capacity and tumorigenic proficiency by coordinating mitochondrial dynamics and mitochondrial-nuclear signaling. Inhibiting σ1R with synthetic antagonists and RNA interference led to the progressive exhaustion and loss of tumorigenicity of the CSC progeny. Mechanistically, interfering with σ1R function disrupted mitochondria homeostasis and triggered β-catenin degradation. Examining clinical CRPC samples, we found a tight correlation between σ1R and mitochondrial gene expression. Furthermore, σ1R and β-catenin protein levels were highly correlated in prostate tumors with significant upregulation in metastatic CRPCs, sustaining a role of the σ1R-mitochondria-β-catenin axis in disease progression. This σ1R-centered axis is essential for preserving the self-renewal and tumorigenic capability of CSCs and represents a critical vulnerability exploitable for discovering novel CSC-directed therapies.
    DOI:  https://doi.org/10.1038/s41388-025-03541-7
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